Inflammatory bowel disease and inflammation-associated colon cancer are major public health problems and effective treatments to treat or prevent these diseases have been lacking in part due to an incomplete understanding of disease pathogenesis. Nlrp6, which belongs to a family of pattern recognition receptors involved in the recognition of microbial and damage signals, has been demonstrated to be protective against colitis and tumorigenesis. Bone marrow chimera experiments have suggested that expression of Nlrp6 in the hematopoietic compartment contributed to protection against inflammation-associated tumor development in mice; however, what specific cell population(s) are responsible for this Nlrp6-dependent phenotype remain unidentified. We now have preliminary data suggesting that inflammatory monocytes are important for Nlrp6-mediated protection against colitis. Since Nlrp6 has been shown to regulate inflammatory responses, IL-18 production, and the composition of the gut microbiota, we hypothesize that Nlrp6 activity in inflammatory monocytes regulates intestinal homeostasis by promoting epithelial repair and modulating the composition of the gut microbiota. Our central hypothesis will be tested by the following specific aims: 1) to determine the mechanism by which Nlrp6 activity in Ly6Chi inflammatory monocytes protects against DSS-induced colitis and colitis- associated tumorigenesis and 2) to investigate whether Nlrp6 function in inflammatory monocytes regulates the gut microbiome in response to inflammation. Our studies will further clarify mechanisms by which Nlrp6 limits inflammation and tumorigenesis, which may lead to new strategies for prevention or treatment.